Nose drops



Patented Jan. 12, 1954 lhttdtli UNITED STATES PATENT DFFICE NOSE DROPS Edgar A. Ferguson, Jr., Brooklyn, N. Y.

No Drawing. Application October 2, 1950,

.. Serial No. 188,063

7Claims.

This invention relates to a new and improved therapeutic agent for local topical application in the treatment of the mucous membrane when irritated and/or infected incident to common colds, allergic rhinitis, etc., and is more particularly concerned with the production of isotonic nose dropscomposition's highly useful in the indicated conditions.

It is an object of the invention to produce and provide isotonic nose drops compositions effective to stimulate granulation tissue in the crevices and bruised portions of the nose which occur on the mucous membrane and in the sinuses during infections commonly referred to as colds.

Excessive secretion from the mucous membrane causes great exfoliation, excoriation, bruising, and erythematous irritation of the membrane. The present invention seeks, therefore, to provide compositions effective, upon local topical application, to soothe and stimulate the healing process on the surface of the mucous membranes of the nose and the nasopharnyx, and thus counteract and reduce irritating and caustic nature of the catarrhal exudate associated with the foregoing conditions.

' In accordance with the present invention, it has now been discovered that a particular mixture of amino acids and polypeptides may be provided which, when brought into contact with the mucous membrane of the nose and the nasopharnyx in the form of an isotonic water solution, causes the catarrhal exudate to subside and soothes and stimulates the healing process.

" It has been determined, further in accordance with the invention, that the usual combination of so-called essential amino acids found in conventional protein hydrolysates not satisfactory for this purpose. This usual amino acid mixture, which is the result of enzymatic digestion or acid digestion of milk protein or milk caseinor yeast.

proteins, contains argenine, histidine, lysine, ty-

rosine,. tryptophane, phenylalanine, cystine,

methionine, threonine, leucine, isoleucine, and valine.

"A study of these amino acids separately has shown that some are partly beneficial, some are indifferent in their effect, and some irritate; but none alone are completely satisfactory in mucous membrane therapy. A study made of the efiect Amino acid Efiect Indifierent. Slight irritation. Indifferent. Do.

Slightly beneficial. Do. Slightly irritating.

'erent. Slightly beneficial.

The discovery that certain of the amino acids in the combinattion caused irritation, led to the formation of a novel complex from which significant amounts of methionine, cystine and histidine, together with certain water-insoluble components, have been removed. This novel complex, containing a particular amino acid mixture, along with polypeptides and unreacted proteins, is the basis of the present invention and the essential ingredient of final therapeutic agent.

The active principle of the new therapeutic agent for local application in the treatment of irritated mucous membrances is composed of a specially prepared protein digest containing a particular mixture of amino acids and polypeptides, and is prepared by subjecting a protein such as lactalbumin to conventional hydrolysis, treating the hydrolysate in a special way to remove-undesirable amino acids and some of .the more water-insoluble fractions of the digested protein, and then further digesting and dehydrating by heat. 7 i

The lactalbumin used consists of plain untreated lactalbumin derived from milk. The analysis of thelactalbumin used for the majority of the tests was as follows: protein 82.5%, ash 8.2 moisture 2.6%, the remainder consisting of certain carbohydrate materials which are eliminated by filtration during the process of hydrolysis.

The initial ste in'the process consists in the formation of lactalbumin hydrolysate, in a con-- ventional manner, by enzymatic digestion with pork pancreas. The menstruum for digestion consists of a 10% solution of one normal hydro- 5 6 of blood was added to each. The tubes were Percent shaken once to thoroughly mix the blood with 2. Desoxyphedrine 0.6 the solution. Tubes were returned to the rack Methylparabene 0.1 and allowed to stand for a period of 20 minutes. Specially treated protein hydrolysate 9.0 Standards were made with distilled water and 5 Neosynephrme hydr chl rid l 05 0.85% solution of sodium chloride. While stand- Sodium sulphite O ing the solid portions containing cells settled a to the bottom in those tubes which were not Ethylenedlamm s e iall a hemolyzed. In the tubes where partial hemolysis 1 Z f j i i i ii f l 1 1'8. ll1 occurred some solid particles settled to the bot- 1o f ifi fi fi f fif me a m y e tom while the supernating fluid was red instead of clear. There was an intermediate layer of I 019411111 cloudy material in partially hemolyzed tubes. N P COmFOSItIOII Which omprlses an Where complete hemolysis occurred the h l isoton c solution of the lactalbumin hydrolysate tube was red and there was no solid material of (11mm 2 Whose ammo acid content is p to settle. Each tube showed three layers, the mately as follows: top layer which was always fluid, the center Per cent layer which was a mixture of fluid and cell ma- Ar i e 3.5 terial and the bottom layer which consisted of Hlstidlne 1 agglutinate and cells, all solid. Ly ine 3 The results were tabulated as follows: yros ne 5 Top layer (fluid) ggg g qg ggglgygg fg Percent $5 1 6 Color Consistency 0021 32? Color gg z Red Clear.

Packed. Cloudy. Do. Packed Do. Do. Do. do... Do. Light red do D0. Red Partly cloudy. Do. do Cloudy Do.

Specially prepared solution of lactalbumin hydrolysates.

This table demonstrates that. 10% solutions of Per cent the specially prepared protein hydrolysate are Trypopnane 2.3 almost perfectly isotonic. The range from 9 to Phenylalanine 5.6 11% sufliciently protects the red blood cells so Cystine 1 that this may be regarded as the range within thio ne 0.6 which isotonicity exists. {V Se e 4.9

While an isotonic water solution of the spe- Threonine '5.0 cially prepared protein hydrolysate may be used Leucine 15 per se as the nose drops composition, it should Valine 4 be understood that other substances may be Alanine 0.1

added. This will cause an increase in osmotic pressure, so the increase must be compensated for by a reduction in the amount of hydrolysate used to render the solution isotonic. In solu tions in which ephedrine hydrochloride is partly neutralized by sodium bicarbonate, the formation of sodium chloride causes a partial osmotic pressure to be developed. If this were in the order of 0.3% sodium chloride it would be necessary to decrease the amount of hydrolysate by about 3%. It will be noted that the osmotic pressure of 0.1% of sodium chloride is roughly equivalent to 1% of specially treated protein hydrolysate. A typical formula would include some perservative in the form of sodium benzoate, a vasoconstrictor such as ephedrine chloride, a neutralizer such as sodium bicarbonate, and the specially treated protein hydrolysate. Typical water-solution formulas contain the following:

Per cent 1. Ephedrine hydrochloride 1 Sodium bicarbonate 0.3 Sodium benzoate 0.1

Specially treated protein hydrolysate 6.0

2. Nose drops composition which comprises an isotonic solution of lactalbumin which has been subjected to substantial hydrolysis to yield a hydrolysate initially containing organized protein and therapeutically efiective amounts of a plurality of free, simple amino acids, including tryptophane, phenylalanine, leucine and valine, specific in their topical application to alleviate symptoms of irritated mucous membrane, admixed with mucous-membrane-irritating amounts of methionine, histidine and cystine, said hydrolysate being subsequently heat-modified to decrease the organized protein content to less than 1%, and reduce said methionine content to the order of 0.4% to 0.8%, the histidine content to below 1% and the cystine content to below 2%.

3. Nose drops composition which comprises an isotonic solution carrying 9% to 11% lactalbumin which has been subjected to substantial hydrolysis to yield a hydrolysate initially containing organized protein and therapeutically effective amounts of a plurality of free, simple amino acids, including tryptophane, phenylalanine, leucine and valine, specific in their topical application to alleviate symptoms of irritated a mucous membrane, admixed with mucousmembrane-i-rritatingamounts of methionine,--- histidine andcysti-ne; said hydrolysate heing subsequently heap-modified" to: decrease the organized. protein content to'l'essthan 1% and redime said methionine content to the, order of 05% to; 028%, the histidine content-to,-below-1% and the icystine; content to below 2%..

4. Nose drops composition which comprisesan isotonic solution carrying aboutt103% of Iactalbumin which has been subjected to substantial hydrolysis to yield a hydrolysate initially containing organized proteinand therapeutically effective amounts of a plurality or free; simple aminoacids; including tryptophane, phenylalanine, leucine and valine, specificiwthein-topical-application to alleviate symptoms of irritated mucous membrane; admixed with-mucous membrains-irritating amounts of methionine, his---- tidine-a-nd cystine, said hydrolysa-te being s'ulosequently heat-modified-- todecrease the organized protein content to less than 1%, and reduce said methionine content to the order of 0.4% to. 0.8%, the histidine content to below 1% andithe.

said' hydrolysate being subsequently hcat-modifled to decrease the organized protein content to less than 1%, and reduce said methionine content to the order of 0.4% to 0.8%, thev histidine content to below 1% and the cystine content to below 2%.

inembrana- =fied to decrease tlie organized protein contenfitw less than 1 and rediice said metliionine-content to -tl'ie order or 024%.15'0'02875 the-h'istidiiie con' tenttdbelow' 1 and the cys't'ifie content-te ts low 2")3.

'7. Nose drops composition wnicn eempfisesan isotonic sonata of'a'pproximately 05 levemeta-methylamino .ethanolphenol hydrochloride, approximately 0.05% sodium sulfite, approximately 0i05;% ethylenediamine and approximate- 1y 10-.0%-lacta-lbu-mirr-which hasbeen subjected". to substantiaL hydrolysis. to; yield a hydrolysate initially-containing organized proteinand therapeuticallyefiective amourits'ofal plurality crrree, simply amino. acids; including tryptophanetphen ylalanine, leucine andizvaline, specific in th'eirf;

topical application to alleviate symptoms of irrietated mucousr-membrane-,= admixedwithmucouss I membrane irritating' amonntsof methioninahistticiine and cystine, said hydrolysate. being sub-i s'equently heat-modifieditonecrease'the organized; proteinc'ontent to less-than 1% ,tandredaucesaidgz methionine'content tothe- Order-of-OA to 0.8% the histidine' content 'to below: l-%-and the=.cystine C0I1tei1t 'tE1'.bBl0W?2%5x p w EDGAR ;A-.'-: EERGUSQN Ja..

References; Cited' the. .filelnfi this. atent LudwigcRepertoriurm Pharmazeutischenspezi alpraparate 1948 Beobachtes:.-A. .SkBaselgpag s 5234524.. 

2. NOSE DROPS COMPOSITION WHICH COMPRISES AN ISOTONIC SOLUTION OF LACTALBUMIN WHICH HAS BEEN SUBJECTED TO SUBSTANTIAL HYDROLYSIS TO YIELD A HYDROLYSATE INITIALLY CONTAINING ORGANIZED PROTEIN AND THERAPEUTICALLY EFFECTIVE AMOUNTS OF A PLURALITY OF FREE, SIMPLE AMINO ACIDS,INCLUDING TRYPTOPHANE, PHENYLALANINE, LEUCINE AND VALINE, SPECIFIC IN THEIR TOPICAL APPLICATION TO ALLEVIATE SYMPTOMS OF IRRITATED MUCOUS MEMBRANE, ADMIXED WITH MUCOUS-MEMBRANE-IRRITATING AMOUNTS OF METHIONINE, HISTIDINE AND CYSTINE, SAID HYDROLYSATE BEING SUBSEQUENTLY HEAT-MODIFIED TO DECREASE THE ORGANIZED PROTEIN CONTENT TO LESS THAN 1%, AND REDUCE SAID METHIONINE CONTENT TO THE ORDER OF 0.4% TO 0.8%, THE HISTIDINE CONTENT TO BELOW 1% AND THE CYSTINE CONTENT TO BELOW 2%. 